Intellectual disability, autosomal recessive 45

Summary

Intellectual disability, autosomal recessive 45 (MONDO:0014430) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 7

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal recessive 45
Mondo ID	MONDO:0014430
OMIM	615979
DOID	DOID:0081209
UMLS	C4014864
MedGen	863301
GARD	0022567
Is cancer (heuristic)	no

Also known as: autosomal recessive non-syndromic intellectual disability caused by mutation in FBXO31 · FBXO31 autosomal recessive non-syndromic intellectual disability · intellectual disability, autosomal recessive 45 · intellectual disability, autosomal recessive type 45 · mental retardation, autosomal recessive 45 · mental retardation, autosomal recessive type 45 · MRT45

Data availability: 7 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › non-syndromic intellectual disability › autosomal recessive non-syndromic intellectual disability › intellectual disability, autosomal recessive 45

Related subtypes (67): intellectual disability, autosomal recessive 1, intellectual disability, autosomal recessive 2, intellectual disability, autosomal recessive 3, intellectual disability, autosomal recessive 12, intellectual disability, autosomal recessive 5, intellectual disability, autosomal recessive 6, intellectual disability, autosomal recessive 7, intellectual disability, autosomal recessive 9, intellectual disability, autosomal recessive 10, intellectual disability, autosomal recessive 11, intellectual disability, autosomal recessive 4, intellectual disability, autosomal recessive 13, intellectual disability, autosomal recessive 14, Rafiq syndrome, intellectual disability, autosomal recessive 16, intellectual disability, autosomal recessive 18, intellectual disability, autosomal recessive 31, intellectual disability, autosomal recessive 29, intellectual disability, autosomal recessive 27, intellectual disability, autosomal recessive 33, intellectual disability, autosomal recessive 30, intellectual disability, autosomal recessive 19, intellectual disability, autosomal recessive 23, intellectual disability, autosomal recessive 24, intellectual disability, autosomal recessive 25, intellectual disability, autosomal recessive 28, intellectual disability, autosomal recessive 34, intellectual disability, autosomal recessive 42, intellectual disability, autosomal recessive 43, intellectual disability, autosomal recessive 44, intellectual disability, autosomal recessive 46, intellectual disability, autosomal recessive 47, Al-Raqad syndrome, intellectual disability, autosomal recessive 50, intellectual disability, autosomal recessive 51, intellectual disability, autosomal recessive 52, intellectual disability, autosomal recessive 54, intellectual disability, autosomal recessive 56, intellectual developmental disorder, autosomal recessive 74, intellectual disability, autosomal recessive 57, intellectual disability, autosomal recessive 58, intellectual disability, autosomal recessive 59, pontocerebellar hypoplasia type 1, intellectual disability, autosomal recessive 64, intellectual disability, autosomal recessive 65, intellectual developmental disorder, autosomal recessive 73, intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly, intellectual disability, autosomal recessive 61, intellectual developmental disorder, autosomal recessive 76, intellectual developmental disorder, autosomal recessive 77, intellectual disability, autosomal recessive 66, intellectual developmental disorder, autosomal recessive 67, intellectual developmental disorder, autosomal recessive 68, intellectual developmental disorder, autosomal recessive 69, intellectual developmental disorder, autosomal recessive 70, intellectual developmental disorder, autosomal recessive 71, intellectual developmental disorder, autosomal recessive 72, glycosylphosphatidylinositol biosynthesis defect 16, intellectual disability, autosomal recessive 60, intellectual disability, autosomal recessive 63, adenosine kinase deficiency, intellectual developmental disorder, autosomal recessive 78, intellectual developmental disorder, autosomal recessive 79, intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly, intellectual developmental disorder, autosomal recessive 81, intellectual developmental disorder, autosomal recessive 82, intellectual developmental disorder, autosomal recessive 83

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

7 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 1 pathogenic/likely pathogenic, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1344806	NM_024735.5(FBXO31):c.1000G>A (p.Asp334Asn)	FBXO31	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
155905	NM_024735.5(FBXO31):c.847_852delinsA (p.Cys283fs)	FBXO31	Pathogenic	no assertion criteria provided
3376842	NM_024735.5(FBXO31):c.842+1G>A	FBXO31	Likely pathogenic	criteria provided, single submitter
1029919	NM_024735.5(FBXO31):c.1348G>A (p.Val450Met)	FBXO31	Uncertain significance	criteria provided, multiple submitters, no conflicts
1029920	NM_024735.5(FBXO31):c.996+4A>G	FBXO31	Uncertain significance	criteria provided, multiple submitters, no conflicts
1034068	NM_024735.5(FBXO31):c.638C>A (p.Pro213His)	FBXO31	Uncertain significance	criteria provided, single submitter
1034069	NM_024735.5(FBXO31):c.44G>A (p.Gly15Glu)	FBXO31	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
FBXO31	Strong	Autosomal recessive	intellectual disability, autosomal recessive	6
FBXO5	Strong	Autosomal recessive	intellectual disability, autosomal recessive	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FBXO31	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FBXO5	HGNC:13584	ENSG00000112029	Q9UKT4	F-box only protein 5	gencc,clinvar
FBXO31	HGNC:16510	ENSG00000103264	Q5XUX0	F-box only protein 31	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FBXO5	F-box only protein 5	Regulator of APC activity during mitotic and meiotic cell cycle.
FBXO31	F-box only protein 31	Substrate-recognition component of the SCF(FBXO31) protein ligase complex, which specifically mediates the ubiquitination of proteins amidated at their C-terminus in response to oxidative stress, leading to their degradation by the proteas…

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FBXO5	Other/Unknown	no		F-box_dom, ZF_ZBR, FBX5_43
FBXO31	Other/Unknown	no		F-box_dom, F-box-like_dom_sf, FBXO31/39

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ganglionic eminence	1
secondary oocyte	1
ventricular zone	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FBXO5	225	ubiquitous	marker	ventricular zone, ganglionic eminence, secondary oocyte
FBXO31	261	ubiquitous	marker	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FBXO5	2,844
FBXO31	634

Intra-cohort edges

A	B	Sources
FBXO31	FBXO5	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FBXO5	Q9UKT4	3
FBXO31	Q5XUX0	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mitotic Metaphase/Anaphase Transition	1	1903.3×	0.004	FBXO5
Phosphorylation of Emi1	1	713.8×	0.005	FBXO5
G1/S-Specific Transcription	1	178.4×	0.011	FBXO5
Regulation of APC/C activators between G1/S and early anaphase	1	154.3×	0.011	FBXO5
SCF-beta-TrCP mediated degradation of Emi1	1	119.0×	0.012	FBXO5
Neddylation	1	23.7×	0.049	FBXO31
Antigen processing: Ubiquitination & Proteasome degradation	1	18.6×	0.053	FBXO31

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of DNA endoreduplication	1	4213.0×	0.002	FBXO5
negative regulation of mitotic metaphase/anaphase transition	1	2106.5×	0.002	FBXO5
negative regulation of ubiquitin-protein transferase activity	1	2106.5×	0.002	FBXO5
positive regulation of mesenchymal stem cell migration	1	2106.5×	0.002	FBXO5
spindle assembly involved in female meiosis I	1	1685.2×	0.002	FBXO5
negative regulation of ubiquitin protein ligase activity	1	1685.2×	0.002	FBXO5
DNA damage response	2	53.5×	0.002	FBXO5, FBXO31
protein ubiquitination	2	41.4×	0.002	FBXO5, FBXO31
positive regulation of biomineral tissue development	1	1404.3×	0.002	FBXO5
negative regulation of meiotic nuclear division	1	1053.2×	0.003	FBXO5
vesicle organization	1	561.7×	0.004	FBXO5
mitotic G1 DNA damage checkpoint signaling	1	526.6×	0.004	FBXO31
microtubule polymerization	1	443.5×	0.005	FBXO5
signal transduction in response to DNA damage	1	401.2×	0.005	FBXO31
anaphase-promoting complex-dependent catabolic process	1	351.1×	0.005	FBXO31
negative regulation of cellular senescence	1	324.1×	0.005	FBXO5
regulation of mitotic nuclear division	1	312.1×	0.005	FBXO5
oocyte maturation	1	300.9×	0.005	FBXO5
positive regulation of G2/M transition of mitotic cell cycle	1	300.9×	0.005	FBXO5
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process	1	187.2×	0.007	FBXO31
regulation of DNA replication	1	183.2×	0.007	FBXO5
regulation of mitotic cell cycle	1	120.4×	0.010	FBXO5
positive regulation of osteoblast differentiation	1	112.3×	0.010	FBXO5
cellular response to oxidative stress	1	77.3×	0.015	FBXO31
proteasome-mediated ubiquitin-dependent protein catabolic process	1	26.1×	0.041	FBXO31
cell division	1	23.1×	0.044	FBXO5
positive regulation of cell population proliferation	1	16.8×	0.059	FBXO5

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FBXO5	0	0
FBXO31	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	FBXO5, FBXO31

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
FBXO5	0	—
FBXO31	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.